Production of 16-dehydropregnenolone and related compounds

ABSTRACT

16-Dehydropregnenolone or 16-dehydroprogesterone is produced by cleavage of the Delta 20(22) double bond in pseudodiosgenin diacetate or pseudodiosgenone acetate by means of photo-oxidation with singlet oxygen in the presence of hematoporphyrin dye.

nitcd States Patent [191 Huber et a1.

[ Oct. 23, 1973 PRODUCTION OF 16-DEHYDROPREGNENOLONE AND RELATEDCOMPOUNDS Inventors: Joel E. Huber; John M. Beaton,

both of Kalamazoo, Mich.

Assignee: The Upjohn Company, Kalamazoo,

Mich.

Filed: Nov. 4,1971

Appl. No.: 195,21

us. Cl 204 158 R int. Cl c071) 29 0 (307C 173/00 Field of Search 204/158R References Cited UNITED STATES PATENTS 11/1970 Huber 204/158 R OTHERPUBLICATIONS Wall et al., J. Amer. Chem. Soc. 77, 5665-5668, 11/55.

Primary Examiner-F. C. Edmundson Attorney-John Kekich et al.

2 Claims, No Drawings PRODUCTION OF l6-DEI-IYDROPREGNENOLONE AND RELATEDCOMPOUNDS BACKGROUND OF THE INVENTION l6-Dehydropregnenolonel6-dehydro-A-pregnene- 3B-oI-20-one) has the following formula:

It is the starting material for the manufacture of a number ofcommercially important steroids. In the past it has been prepared byreacting the 16-cyano analog with methyl Grignard reagent.

Pseudodiosgenin diacetate has the following formula:

following compound III:

CH; (11 0 to 3 AcO III

Heating III with acid or alkali converts it to l6-dehydropregnenolone.Other oxidizing agents have been used to produce III (Wall, et al.,J.A.C.S. 77, 5665). Overall yields of greater than 55 percent based onthe diosgenin starting material can be obtained by careful manipulation,but the average industrial yield is approximately 45 percent.

BRIEF DESCRIPTION OF THE INVENTION According to the invention II isdissolved in an organic solvent in a reaction zone provided with aninlet for oxygen positioned in such a way that the oxygen entering thereaction zone is exposed to the illumination of a source of actiniclight such as a fluorescent tube. The reaction is carried out in thepresence of hematoporphyrin dye and in the further presence of aceticanhydride. After the oxygenation has been completed as indicated by thedisappearance of starting material from the reaction zone, the productis separated from the residual solvent and reactants by known methods,and finally hydrolyzed by contacting with aqueous alkali.

In the 7 conversion of pseudodiosgenone to l6-dehydroprogesterone theforegoing conditions can be followed.

The novel reaction of this invention has a variety of advantages. Ofsignificance is the fact that the conditions of oxygenation are milderthan those previously used in the art employing chromium trioxide, henceother molecular substituents on the molecule are considerably lesssubject to oxidative attack.

A further significant advantage of the reaction of chromium process ofthis invention is the elimination of chromifm compounds and the chromiumion as byproducts of the reaction. Recovery of such heavy metalby-products or their chemical conversion to chemical states that arenon-toxic to plant and animal life is dietated by considerations oftechnology and ecology.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 Photo-oxygenation ofpseudodiosgenin diacetate A solution of 10.00 g. of pseudodiosgenindiacetate and 25 mg. of hematoporphyrin dye in 10 ml. of aceticanhydride, 10 ml. of pyridine and 50 ml. of dry acetone was placed in a2.5 X 60 cm. pyrex tube fitted with a medium porosity fritted disk atthebottom and a cold finger mounted at the top which extended through thecenter of the tube to the fritted disk. Oxygen was passed through thedisk at a rate of 0.2 cu. ft./hr. while the tube was being illuminatedwith four 15-watt fluorescent tubes. The temperature was maintained atl5-20 throughout the 2 hr. reaction.

The disappearance of starting material by thin layer chromatography(silica gel, 30 percent ethyl acetate in Skelly-solve B hexanes) wasused to judge the end of the reaction. The acetone was removed in vacuoat 30 leaving a red oil which was dissolved in 300 ml. of benzene. Thissolution was washed with 50 ml. of water, twice with 150 ml. portions ofsaturated sodium carbonate, twice with 100 ml. portions of water, twicewith 100 ml. portions of 3N hydrochloric acid, and twice more with 100ml. portions of water. The organic layer was concentrated in vacuo toafford a higher boiling oil which was dissolved in ml. of isopropanoland refluxed under nitrogen for one-half hour. To this solution wasadded 60 ml. of 7 percent aqueous potassium hydroxide.

The saponification was complete after 10 min. reflux under nitrogen. Thevolume of the reaction mixture was reduced to approximately 100 ml. bydistillation in vacuo. The addition of 75 ml. of water provided aprecipitate which was collected by filtration, dried at in wsyploxidation which comprises reacting in a reaction zone an organic solventsolution of a member of the group consisting of pseudodiosgenindiacetate and pseudodiosgenone acetate, respectively, with oxygen in thepresence of hematoporphyrin dye and acetic anhydride while irradiatingthe reaction mixture in such a way that the oxygen entering the reactionzone is exposed to illumination with actinic light, and hydrolyzing thereaction product with aqueous alkali.

2. The method of claim 1 in which 16-dehydropregnenolone is produced bymeans of photooxygenation of pseudodiosgenin diacetate with singletoxygen.

* k 1F i

2. The method of claim 1 in which 16-dehydropregnenolone is produced by means of photooxygenation of pseudodiosgenin diacetate with singlet oxygen. 